Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.
(2012) In Neurobiology of Disease 45(3). p.939-953- Abstract
- Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound... (More)
- Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2273867
- author
- Decressac, Mickael LU ; Mattsson, Bengt LU ; Lundblad, Martin LU ; Weikop, P and Björklund, Anders LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- alpha-Synuclein, Parkinson's disease, Adeno-associated viral vector, Motor deficit, Rat
- in
- Neurobiology of Disease
- volume
- 45
- issue
- 3
- pages
- 939 - 953
- publisher
- Elsevier
- external identifiers
-
- wos:000300519600012
- pmid:22182688
- scopus:84856570373
- pmid:22182688
- ISSN
- 0969-9961
- DOI
- 10.1016/j.nbd.2011.12.013
- language
- English
- LU publication?
- yes
- id
- f4fbd410-1c55-4b00-bd81-571ea4f0ce39 (old id 2273867)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/22182688?dopt=Abstract
- date added to LUP
- 2016-04-01 11:03:22
- date last changed
- 2022-04-28 06:47:35
@article{f4fbd410-1c55-4b00-bd81-571ea4f0ce39, abstract = {{Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.}}, author = {{Decressac, Mickael and Mattsson, Bengt and Lundblad, Martin and Weikop, P and Björklund, Anders}}, issn = {{0969-9961}}, keywords = {{alpha-Synuclein; Parkinson's disease; Adeno-associated viral vector; Motor deficit; Rat}}, language = {{eng}}, number = {{3}}, pages = {{939--953}}, publisher = {{Elsevier}}, series = {{Neurobiology of Disease}}, title = {{Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.}}, url = {{http://dx.doi.org/10.1016/j.nbd.2011.12.013}}, doi = {{10.1016/j.nbd.2011.12.013}}, volume = {{45}}, year = {{2012}}, }